tbuckley/cabot-search huggingface dataset:
Real world (rw) homologous recombination repair (HRR) gene mutation testing trends in patients (pts) with metastatic castrate-resistant prostate cancer (mCRPC) in the United States (US).
Authors: Pedro C. Barata, Rachel Montgomery, Matthew Last, Liane Gillespie-Akar, Jonathan Nazari, Bhakti Arondekar, Alexander Niyazov
Journal: Journal of Clinical Oncology (2023)

98 Background: Previous research suggests that HRR mutations may have prognostic value in mCRPC. Additionally, HRR mutations are therapeutically relevant and can inform treatment decisions. Limited information is available on HRR mutation testing rates in the US. This study assessed rw HRR testing patterns in pts with mCRPC in the US and described characteristics associated with HRR testing. Methods: Retrospective data from pts with mCRPC initiating first line (1L) treatment between 2014 – 2021 was obtained from the nationwide Flatiron Health electronic health record-derived de-identified database. Pt demographic and clinical characteristics were summarized descriptively across subgroups by HRR gene testing status (tested vs not tested). A multivariable logistic regression model was used to assess factors associated with receiving HRR testing, and included covariates for demographic, clinical, and treatment characteristics. Results: A total of n=8,166 pts with mCRPC receiving 1L treatment were identified. The mean age of the cohort was 72.9 (standard deviation (SD) 8.1) years. Overall, 2,122/8,166 (26%) were known to have received HRR mutation testing. Pts who did not receive HRR testing were older compared to HRR tested pts (mean age 73.7 (SD 8.5) vs 70.6 (SD 7.5) years). A higher proportion of HRR tested were receiving treatments from an academic medical center vs community practice (14.5% vs. 7.7%). Multivariable logistic regression indicated age &gt; 65 (vs &lt; 65 years), Black race (vs White), being treated in the community (vs academic), and having de novo metastatic disease (vs recurrent) were associated with a statistically significant lower odds of HRR mutation testing. In contrast, a higher socioeconomic status and being diagnosed with mCRPC after 2018 were associated with a statistically significant increased odds of HRR mutation testing. Conclusions: In this rw study, a minority of US pts with mCRPC received HRR mutation testing. Disparities in HRR mutation testing exist, and focused efforts to increase HRR testing should be developed, especially among Black pts, pts with lower socioeconomic status, pts treated in the community setting, and pts &gt; 65 years of age. [Table: see text]
Prevalence of HRR gene mutations in patients with metastatic castration-resistant prostate cancer: Germline results from the Latin-American observational study PROSPECT.
Authors: Ray Manneh Kopp, Carmen Alaez Verson, Martin Angel, Arturo Delgado, Pedro H Isaacsson Velho, Alejandro Manduley, Melissa Barbieri, Carmen Vargas, Francisco Gonzalez, Pedro C. Barata
Journal: Journal of Clinical Oncology (2023)

226 Background: Metastatic castration-resistant prostate cancer (mCRPC) is a molecularly heterogeneous disease, and 20% to 30% of patients harbor alterations in homologous recombination repair (HRR) genes. However, data regarding the genetic profile of mCRPC in Latin American populations are scarce. This study determined the prevalence of HRR gene mutations in Latin American patients with mCRPC to better understand this population and guide future policies. The interim analysis herein reports results focused on germline alterations only. Methods: PROSPECT (NCT04962880) is a cross-sectional, non-interventional, multicenter study. Patients were adults (≥18 years) diagnosed with mCRPC from November 2020 to October 2021 at centers in Argentina, Brazil, Colombia, Costa Rica, Mexico, Panama, and Peru. Diagnoses were confirmed by laboratory testing (PSA and/or testosterone levels) or imaging (X-ray, CT, MRI, or PET scan). All patients provided written informed consent. Blood samples were assayed to determine the prevalence of germline mutations in HRR genes in the participating countries using the AmoyDx HANDLE HRR Next Generation Sequence 32 genes Panel (AmoyDx, Xiamen, China). Results: Overall, 388 participants with a median age of 70 years (range: 49‒89) were included in this study, including 184 Hispanic (47.4%), 101 White (26%), 40 Mestizo (10.3%), 11 African American (2.8%), 2 Asian (0.5%), and 50 “other” (12.9%) patients. Over a third of them (n=151, 38.9%) had a family history of cancer. Median time since prostate cancer diagnosis was 3 years (range: 0‒23) and 2 years (range: 0‒22) since mCRPC diagnosis. Metastases were most frequently localized to the bones (59.6%). The patients’ ECOG status was either 0 (173/365; 47.4%) or 1 (192/365; 52.6%). Among the 167 patients that received treatment, most received androgen deprivation therapy alone (43.7%) or with radiotherapy (21.6%). Overall, 25/381 patients (6.56%) had germline HRR mutations. The 5 most frequently mutated HRR genes were BRCA2 (16%), ATM (12%), CHEK2 (12%), BRIP1 (8%) and HOXB13 (8%). Conclusions: The prevalence of germline HRR mutations found in this multinational Latin American population was lower than expected compared to previously reported rates ranging from 8% to 12% from other countries. Additionally, the most frequently mutated HRR genes differed from those from major trials including PROfound (NCT02987543). Clinical trial information: NCT04962880 . [Table: see text]
Randomized phase II study of olaparib (Ola) maintenance following cabazitaxel-carboplatin induction chemotherapy (CabCarb) in men with aggressive variant prostate cancer (AVPC).
Authors: Patrick Glen Pilié, Rebecca Slack Tidwell, Paul Vincent Viscuse, Sumit Kumar Subudhi, Paul Gettys Corn, Shi-Ming Tu, John C. Araujo, Amado J. Zurita, Jennifer Wang, Eleni Efstathiou, Jessica Deinert, Christopher Logothetis, Timothy C. Thompson, Ana Aparicio
Journal: Journal of Clinical Oncology (2023)

196 Background: An aggressive subset of prostate cancers (AVPC) respond poorly to androgen signaling inhibitors, have limited therapeutic options and a dismal prognosis. Preclinical models of AVPC display functional alterations in DNA damage response (DDR) pathways linked to platinum and PARP inhibitor (PARPi) sensitivity. We hypothesized that PARPi (ola) maintenance following CabCarb would improve the progression free survival (PFS) of men with AVPC. We performed a tissue-rich randomized trial for men with AVPC to address this hypothesis and unravel the heterogeneity of AVPC by linking genomic and transcriptomic analyses with clinical outcomes. Methods: In a single-institution study, men with CRPC meeting ≥ 1 of 9 AVPC criteria and ECOG performance status (PS) of 0-2 received 6 cycles of Cab 20-25mg/m 2 and Carbo (AUC 3-4). Men completing 6 cycles without progressive disease (PD) were randomized 2:1 to Ola 300mg BID vs. observation (Obs). The primary endpoint is to estimate PFS in those randomized and we aimed to detect a difference of 3.9 vs. 7.8 months. Subgroup comparisons between patients who had PD prior to randomization (platinum-resistant) vs. those randomized (platinum sensitive) were made with chi-square tests for categorical baseline characteristics, and Kruskal-Wallis test for continuous measures. Results: 96 patients started CabCarb. Their median age was 67 years (43-86), most were white/non-Hispanic (74%), had an ECOG score of 0 (64%), bone metastases (79%), and no prior docetaxel therapy (59%). Of the 96, 7 (7.3%) went off study for reasons unrelated to PD and 36 (37.5%) had PD prior to randomization. Patients with PD prior to randomization were more likely at baseline to have received prior docetaxel (59% vs. 29%; p=0.004), have bone metastases (92% vs. 71%; p=0.03), have lower hemoglobin (11.4 vs. 12. 4; p=0.02), higher LDH (359 vs. 260; p=0.01), lower albumin (4.0 vs. 4.2; p=0.04), and higher AlkPhos (181.5 vs. 98.5; p=0.01) compared to patients who went on to randomization. With a median follow up time of 38.9 months post randomization, the median PFS was 2.3 months (95% confidence interval: 1.3, 4.6 months) for Observation and 4.9 (3.5, 6.3) months with Olaparib (p=0.12). The median OS was 16.2 (6.8, 26.4) for observation and 15.3 (10.2, 28.4) months with Olaparib (p=0.56). Conclusions: These data highlight the heterogeneity within the AVPC subset. Ongoing molecular analyses of sequential liquid and tumor tissue will illuminate the underpinnings of this heterogeneity and identify targets for additional combinatorial strategies. Clinical trial information: NCT03263650 .
Biochemical recurrence (BCR) surrogacy for clinical outcomes after radiotherapy for adenocarcinoma of the prostate (BCRSCRAP): A meta-analysis from MARCAP Consortium.
Authors: Soumyajit Roy, Tahmineh Romero, Allison Steigler, James William Denham, David John Joseph, Jeff M. Michalski, Felix Y Feng, Michel Bolla, Theo M. de Reijke, Philippe Maingon, Matthew R. Sydes, David P. Dearnaley, Luca Incrocci, Wilma Heemsbergen, Abdenour Nabid, Luis Souhami, Almudena Zapatero, Yilun Sun, Daniel Eidelberg Spratt, Amar Upadhyaya Kishan
Journal: Journal of Clinical Oncology (2023)

391 Background: Event-free survival, a PSA-driven endpoint, was shown to not be surrogate endpoint for overall survival (OS) in the ICECAP two-stage meta-analytic approach. However, time to biochemical recurrence (TTBCR) in NRG/RTOG 9202 met Prentice criteria for surrogacy. We performed an individual patient data (IPD) meta-analysis of 11 randomized controlled trials evaluating RT dose escalation, ADT use, and adjuvant ADT prolongation to evaluate the surrogacy of time to BCR (TTBCR), censoring for non-prostate cancer deaths, using both approaches to evaluate surrogacy. Methods: This individual patient level meta-analysis was performed using data from the MARCAP consortium, and 11 radiotherapy trials were included. TTBCR was defined as time to developing a BCR or experiencing prostate cancer-specific mortality (PCSM), with censoring at time of other-cause death or loss to follow-up. Landmark analyses were used to test the Prentice criteria for surrogacy. For patient level correlation between TTBCR and OS, we applied a bivariate Copula model to estimate the Kendall’s τ. For trial level correlation of the treatment effect on TTBCR and true endpoints, a weighted linear regression model was applied between the effects of treatment (natural log of hazard ratio [log-HR]) on OS versus TTBCR using a weightage that was inverse variance of BCR log-HR estimate. Results: Based on Prentice criteria, BCR at the landmark time point of 48 months was associated with increased risk of mortality in trials that compared treatment intensification with adjuvant ADT prolongation (HR 2.18 [95% CI 1.95-2.42]), the addition of ADT (HR 1.38 [1.25-1.54]), and RT dose escalation (HR 2.12 [1.83-2.46]) on uni- and multi-variable analyses. At the patient level, there was a low to moderate level correlation between BCR and OS with Kendall’s τ of 0.34 and a R 2 of 0.55 for correlation of treatment effect on TTBCR and OS. At the trial level, there was a poor correlation between treatment effect on TTBCR and OS (R 2 =0.16). Conclusions: This IPD meta-analysis demonstrates that while BCR is prognostic, it is not a surrogate endpoint for OS in localized prostate cancer for patients treated with a diverse array of radiotherapeutic strategies. This highlights the importance of other cause mortality in prostate cancer. Our results highlight the differences in interpretability of Prentice criteria and the two-stage meta-analytic approach and suitability of endpoints for clinical trial design.
AlphaBet: A phase I/II trial evaluating the combination of radium-223 and [<sup>177</sup>Lu]Lu-PSMA-I&amp;T in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Louise Kathleen Kostos, James Patrick Buteau, Theresa Yeung, Sophia Xie, Juliana Di Iulio, Anthony Cardin, Katie Owen, Heidi Fettke, Kwang Y Chin, Brittany Emmerson, Mohammad B Haskali, Belinda Parker, Luc Furic, Arun Azad, Michael S Hofman
Journal: Journal of Clinical Oncology (2023)

TPS280 Background: [ 177 Lu]Lu-PSMA-I&amp;T (LuPSMA) is a small molecule radioligand that delivers radiation via beta-particulate emission to cells expressing prostate-specific membrane antigen (PSMA). Despite a survival benefit in mCRPC, responses for many are not durable, with the majority of pts developing progressive osseous disease. Due to the lack of crossfire radiation in micrometastatic disease, small cancer cell clusters in the bone marrow may not receive an adequate dose of radiation from 177 Lu to induce cytotoxic double-stranded DNA breaks. Alpha-emitters have a shorter path length (≤100 µm) and higher linear energy transfer, making them better suited for treating micrometastatic disease. As a calcium-mimetic, radium-223 ( 223 Ra) is a bone-specific alpha-emitter which targets osteoblastic bone metastases. We hypothesise that the combination of LuPSMA with 223 Ra will be well tolerated and lead to improved response durability. Methods: This phase I/II, single-arm, single-centre study will enrol 36 patients with mCRPC who have progressed on a prior second-generation antiandrogen. Up to 6 cycles of LuPSMA (7.4 GBq) and 223 Ra (28 kBq/kg - 55 kBq/kg) will be given intravenously every 6 weeks, along with background androgen deprivation and bone protective therapy. Key eligibility criteria include a diagnosis of mCRPC with at least two untreated bone metastases visible on bone scintigraphy and PSMA-positive disease on PSMA PET/CT (SUVmax ≥20). Sites of FDG-positive disease must be either PSMA-positive or have increased uptake on bone scan. Other eligibility criteria include an ECOG status of 0-2, and adequate bone marrow and organ function. Patients treated with more than one line of chemotherapy for metastatic prostate cancer are not eligible. Blood samples and biopsies will be taken at baseline, on treatment, and at progression to develop tumor- and immune-based biomarkers that predict treatment response and associated survival benefit. A traditional 3+3 dose-escalation model will be utilized initially, escalating the dose of 223 Ra. The dose of LuPSMA will remain fixed. The co-primary objectives of this study are to determine the maximum tolerated dose of 223 Ra when combined with LuPSMA, and the 50% PSA response rate. Secondary objectives include measuring the frequency and severity of adverse events, assessment of efficacy through overall, radiographic and PSA progression-free survival, overall survival, objective tumor response rate, and evaluation of pain and health-related quality of life. Enrolment commenced in September 2022 and will continue for 24 months. Clinical trial information: NCT05383079 .
Intra-individual dose escalation of abiraterone (ABI) according to its plasma exposure in patients (pts) with progressive metastatic castration-resistant prostate cancer (mRCPC): Results of the OPTIMABI trial.
Authors: Jerome Alexandre, Stephane Oudard, Luca Campedel, Lisa Golmard, Sylvain Ladoire, Ahmed Khalil, Denis Maillet, Christophe Tournigand, Françoise Goirand, Jerome Guitton, Charles Dariane, Florence Joly, Evanguelos Xylinas, Jean Louis Golmard, Hendy Abdoul, Nihel Khoudour, Alicja Puskiel, Edith Carton, Olivier Huillard, Benoit Blanchet
Journal: Journal of Clinical Oncology (2023)

159 Background: Abiraterone acetate (ABI) improves survival in mCRPC. In a previous observational study, worse PSA response and shorter progression-free survival (PFS) were associated with mean ABI plasma through concentration (ABI Cmin) &lt; 8.5 ng/mL within the first three months (ms) of treatment (Carton E et al. Eur J Cancer 2017). The OPTIMABI study, a multicenter non-randomized study (NCT 03458247), aimed to investigate whether a dose escalation of ABI improve PFS in underexposed progressive mCRPC pts. Methods: In step 1, pts with docetaxel-naive progressive mCRPC received ABI at the standard dose of 1000 mg/d + Prednisone 10 mg/d. Mean ABI Cmin was calculated from three monthly dosages. Pts experiencing progression within the first 6 ms and for whom mean ABI Cmin was &lt; 8.5 ng/mL were included in step 2 and received 1000 mg twice daily (2000 mg/d) of ABI. ABI Cmin was assessed every month. The primary endpoint was the non-progression rate at 12 weeks in step 2. Identification of risk factors of 6 ms-PFS was done using Cox regression analysis. Results: From 06/2018 to 09/2021, 81 of 93 pts (median age: 72 yrs) included in step 1 were evaluable for statistical analysis. The median ABI Cmin was 10.0 (IQR: 4.5-15. 0) ng/mL over the first three ms. Inter-individual variability was 59%. The 6 ms-PFS was 68% (IC 95%: 56% - 80%) with no statistical difference between pts with mean ABI Cmin ≥ or &lt; 8.5 ng/mL (log-rank test, p= 0.24). In multivariate analysis, liver metastasis (Hazard ratio, HR = 5.95, CI95% = 1.22–28.92; p=0.027) and creatinine clearance &lt; 60 mL/min (HR = 3.51, CI95% = 1.12–10.99; p=0.031) were independently associated with 6 ms-PFS. Among 21 pts (25.9%), with mean ABI Cmin &lt; 8.5 ng/mL, 8 pts (38.1%) experienced tumor progression within the first 6 ms; four of them could be included in step 2. None of them fulfilled the primary endpoint despite a significant increase in plasma ABI Cmin (p &lt;0.036 by paired t-test). Conclusions: Despite high inter-individual variability of mean ABI Cmin, the OPTIMABI study does not support the strategy of intra-individual dose escalation according to plasma concentration of ABI in mCRPC. Underexposure to ABI (ABI Cmin &lt; 8.5 ng/mL) was not statistically associated with shorter PFS. Clinical trial information: NCT03458247 .
Development and validation of a multigenomic liquid biopsy (PROSTest) for prostate cancer detection.
Authors: Irvin Mark Modlin, Mark Kidd, Ignat A. Drozdov, Martin Boegemann, Lisa Bodei, Jolanta Kunikowska, Anna Malczewska, Christof Bernemann, Kambiz Rahbar
Journal: Journal of Clinical Oncology (2023)

252 Background: A crucial requirement in prostate cancer (PCa) management is an accurate, easily measurable, liquid biopsy that can define the molecular pathology of an individual PCa. We report the development and clinical validation of a novel PCa-specific, multi-genomic biomarker. Methods: We identified candidate mRNA biomarkers in PCa-Adeno transcriptomes ( n=1,159) using several strategies: co-expression networks, differential expression, and functional enrichment. mRNA transcripts were screened in an independent tumor tissue ( n=50) set and validated as biomarkers in the TCGA-PRAD ( n=500) dataset. An amalgam of Random Forest, Gradient Boosted Machines and Support Vector Machines, all standard machine learning classifiers, was used to develop a classification algorithm and probability score in a peripheral blood gene expression test cohort ( n=430). This multigene biomarker was validated in two independent clinical blood sample sets (Set I: PCa n=77, controls n=54; Set II: PCa n=132, controls/BPH n=99) to determine as PCa-specificity and diagnostic efficacy Clinical utility was evaluated versus Gleason scores, T-staging and PSA ( n=209) and in a prostatectomy cohort ( n=47). Results: The pipeline identified 27 of PCa gene markers in the tumor tissue set and TCGA-PRAD dataset. Gene expression was significantly correlated ( r=0.72, p&lt;0.0001) in matched tissue/blood samples. The PROSTest (scale: 0-100) ensemble algorithm (developed in blood) had a sensitivity for PCa of 92.2% (95% CI: 83.8-97.1%; Set I) and 95.0% (95% CI: 89.9-98%. Set II). The specificity was 100% for Set I (95% CI: 93.4-100%) and 100% for Set II (95% CI: 96.3-100%). PCa scores were significantly ( p&lt;0.0001) lower for controls (Set I: 17±4; Set II: 18±4) and BPH (19±6) to PCa; 82±19 (Set I) and 80±19 (Set II). The AUROC was 0.98±0.01. PROSTest scores were elevated ( p&lt;0.05) in T2-4 and were significantly correlated with Gleason ( r=0.93, p&lt;0.02). In contrast, PSA from matched samples was not associated ( p=NS) with clinically significant disease (Gleason 7-10 or T2-4 tumors). In head-to-head comparisons, the PROSTest was considerably more accurate than PSA for detecting significant disease (z-statistic: 2.43, p=0.015). In the R0 prostatectomy cohort, all scores were elevated (72±7) and significantly decreased post-surgery (26±8, p&lt;0.0001, n=37). Individuals with residual disease ( n=10) exhibited elevated (60±4) post-surgical scores. Conclusions: The PROSTEst is a multigenomic blood-based PCR tool that accurately (&gt;90%) identifies prostate cancer. It is significantly more accurate than PSA for the detection and stratification of clinically significant prostate disease. A multigenomic liquid biopsy for PCA provides a real-time, non-invasive method for detection of a PCa and may facilitate the early identification of residual/recurrent disease.
Additional cycles of docetaxel in combination with androgen deprivation therapy (D-ADT) in metastatic hormone-sensitive prostate cancer (mHSPC): Efficacy and feasibility analysis.
Authors: Can Aydogdu, Florian Urban, Alexander Tamalunas, Elena Berg, Melanie Götz, Severin Rodler, Volker Heinemann, Christian Stief, Jozefina Casuscelli
Journal: Journal of Clinical Oncology (2023)

185 Background: Several phase III trials have assessed efficacy and safety of 6 cycles of docetaxel combined to androgen deprivation therapy (ADT). This is the current standard of care for a subgroup of patients. We aimed to assess whether treatment beyond 6 cycles of docetaxel prove to be more effective than the standard of care. Methods: We retrospectively analyzed patients with histologically confirmed adenocarcinoma of the prostate and radiologically proven metastatic disease from a large tertiary care center. All patients with mHSPC were treated in first line with ADT in combination with docetaxel (75 mg/m 2 ) (D-ADT) intravenously on the first day of each 21-day cycle. A subset of patients was treated beyond the standard of 6 cycles. Clinical and pathological variables were analyzed, progression free survival on D-ADT (PFS1), progression free survival on subsequent therapy (PFS2) and overall survival (OS) were the endpoints analyzed by log- rank test. Results: Between 2018-2022 a total of 74 mHSPC patients were followed-up for a median time of 13.7 months. Mean age was 66.2 years (range 50.1-82.4), and 79.7% had GS≥8, 73% a CHAARTED high-volume and 76% LATITUDE high risk disease. 43 pts. were treated with ≤ 6 cycles (D-ADTstand) (2.4 % 1-2 cycles; 97.6 % ≥3 cycles; mean 5.3 cycles) and 31 were treated with &gt;6 cycles docetaxel (D-ADTadd) (25.8 % 7-8 cycles; 74.2% ≥9-10 cycles, mean 9.2 cycles). No significant differences were observed in median PFS1 (12.4 vs. 13.7 mos.) and PFS2 (5.4 vs. 9.6 mos.). Median OS in the D-ADTstand group was 39.8 mos., median OS in the D-ADTadd group was not yet reached. Conclusions: While more than 6 cycles of D-ADT in mHSPC proved to be feasible without significant additional toxicity, efficacy is not superior compared to the standard of 6 cycles. Overall survival data is not mature yet, but the benefit of more chemotherapy upfront is debatable and leverages further studies in light of the upcoming triplet combinations in mHSPC, that presumably will render D-ADT obsolete in future. [Table: see text]